This proposal outlines a 5-year career development plan for Dinesh S. Rao, M.D. in anticipation of a career in academic hematopathology. The principal investigator (P.I.) has completed a structured residency and fellowship training in pathology and hematopathology at UCLA. The structured research training proposed herein will be completed in the laboratory of David Baltimore, Ph.D., at the California Institute of Technology, as part of the UCLA-Caltech STAR program. Dr. Baltimore, the recipient of the Nobel Prize in Physiology or Medicine in 1975, and currently the Robert A. Millikan Professor of Biology and President Emeritus, is a pre-eminent biologist with extensive experience mentoring numerous physician-scientists into academic positions. The P.l.'s career development will benefit from the synergy of the basic scientific environment at Caltech and the medical resources at UCLA. The P.I. will also receive career and scientific advice from a committee of scientists and physicians at UCLA, as well as a thesis committee at Caltech. The overall goal of this proposal is to study the roles of microRNA-34 (miR-34) and B-cell oncogenes in normal and neoplastic B-cell differentiation. The specific hypotheses being tested are: (i) Human lymphomagenesis results from aberrant unrestricted expression of the B-cell oncogenes, c-MYC, BCL2 and BCL6; (ii) miR-34 plays a role in terminal B-cell differentiation by restricting oncogene expression post-transcriptionally; and (iii) Dysregulation of miR-34 mediated downregulation of oncogene expression plays a role in the genesis of B-cell neoplasia. The proposed experiments will entail lentiviral transduction of c-MYC, BCL2 and BCL6 into human CD34+ cells, introduction into mice, and phenotypic analysis of the mice using various molecular, cell biological, biochemical, histologic and other techniques. Using bone marrow transfer experiments, we will examine the role of microRNA-34 in B-cell development. Lastly we will examine if miR-34 mitigates development of B-cell neoplasia in the humanized lymphoma model described above. These studies promise to highlight new mechanisms that effect B-cell development and may lead to important advances in the diagnosis and treatment of lymphoma. RELEVANCE: Lymphomas and leukemias, which are both cancers of white blood cells, are a major cause of suffering and death in numerous Americans each year. By concentrating on the study of human lymphoma, this study attempts to discover new insights into the biological processes that promote their development. Hence, these studies have a direct relevance to public health and most importantly, to patients living with these diseases.